How Broadening the Analysis of Compound Factors Allows for Predictive Solubility Solutions

The Biopharmaceutics Classification System (BCS),

developed by the U.S. Food and Drug Administration to

simplify and accelerate the drug development process,

helps companies when they file for bioequivalence of

dosage forms based on in vitro dissolution testing.

The objective of the BCS system is to predict in vivo

performance of drugs from in vitro measurements of

solubility and permeability. The system has evolved to

classify low-soluble drugs according to their permeability

(BCS Class II or IV). A compound’s classification

(I through IV) is indicative of its potential bioavailability.

Matt Wessel, Marshall Crew,

Sanjay Konagurthu and

Tom Reynolds

SolubilityEnhancementServices

Companies also have adopted the BCS system

as a test for a compound’s oral delivery, leading

decision-makers to believe that knowing a

compound’s solubility (logS) and lipophilicity (logP)

can guide them to the right choice of formulation.

While understandable, relying on these parameters

to identify solubility solutions oversimplifies the

challenge. A Patheon analysis of drugs brought

to market over the past three decades shows that

approved drugs do not follow clear trends when

these two measures alone are considered.

Additional factors can provide a more

complete picture.

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Relying on logS and logP to identify

solubility solutions oversimpliðes the

challenge.

Today’s molecules require additional criteriaAs noted in our recent paper (“How to Choose

the Right Solubilization Technology for Your API”),

recent trends indicate that logS is decreasing and

logP is increasing for new small-molecule medicines.

The reason for this shift is two-fold.

First, improvements in synthetic chemistry and

high-throughput screening have expanded the

small-molecule chemical space that can be

accessed. This expansion has led to more novel

compounds with desirable potency that present

greater solubility challenges. The result: a landscape

with more molecules worth investigating that are

difficult to make effective in vivo.

The second reason for the shift: More emphasis

on compounds that target less “druggable” entities

(such as kinases), which typically require more

lipophilic compounds to capture potency.

With these two factors in play, there are additional

factors to analyze besides logS and logP when

considering a solubility solution, including melting

points, pKa, permeability, a compound’s potency,

and dosage levels. Analysis of these factors, in

combination with the traditional approach of

examining logP and logS, allows us to develop

a method for narrowing the range of potential

solubility solutions a company should consider.

A look back at drug solubility solutions for three

drugs on the market provides a useful illustration.

Similar readings for two properties, but different solubility solutionsA map of compounds as a function of logP and

logS, shown in Figure 1, illustrates the limitations

of the traditional approach of relying on just these

two properties. In the plot, drug products using

dispersion and lipid technologies are shown in red

and black, respectively. As the figure shows, these

two properties alone do not differentiate which

technology is appropriate. There is no discernable

grouping of the compounds in this particular

chemical property space plot.

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Figure 1: LogP/LogS plots for commercial products delivered with dispersions, lipids, nano-crystals, and as pure amorphous drug. Drug products using dispersion are shown in black, and lipid technologies are shown in red. The contours represent the frequency at which molecules fit in a range on the graph, rising from blue to yellow to red.

Source: Data from DrugBank – Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006 Jan 1;34(Database issue): D668-72. 16381955.

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The green circle in Figure 1 surrounds three drugs

that use distinct solubilization technologies. But

while the three drugs – calcitriol, itraconazole, and

posaconazole – essentially have the same logS

and logP values, they have different formulation

and process development histories. By examining

other traits of these compounds, and their histories,

we can derive insights into why they each used

different solubility technologies. (It is worth noting

that itraconazole and posaconazole are structural

analogs that target the same enzyme. Calcitriol was

developed for a different target enzyme and indication.)

The three structures in Figure 2 are commonly-used

drug compounds, but for different indications.

Calcitriol is notably different in structure from the

other two, while itraconazole and posaconazole

are clearly analogs of each other. The structural

differences between calcitriol and the other two

compounds suggest that structure is also a

differentiator with respect to technology. However,

without looking at the respective structures, the

similar logS and logP values for the three

compounds can be misleading.

As can be seen in Table 1, there is very little difference

in the logS and logP values. However, differences in

melting point and pKa are evident. These differences

can be used, in part, to drive rational decisions

regarding formulation choices. The history of the

three compounds bear this out:

Itraconazole uses hot melt extrusion (as

Onmel) and spray-layered coated beads (as

Sporanox). Itraconazole is an antifungal agent also

used for other indications. It comes in two oral

dosage forms, Sporanox and Onmel. Sporanox

(first marketed in 1999) uses spray layered coated

bead technology. The drug, in the form of a solid

dispersion with hydroxypropyl methylcellulose

(HPMC), is spray layered onto spherical sugar beads

to form a solid dispersion.

Spray layering is advantageous in that it can use

conventional, solvent-capable fluid bead processing

equipment (in contrast to spray drying that requires

a specialized process train). A disadvantage with

spray-layered beads is that loading them to meet

larger unit dose levels can be challenging. In fact,

the recommended dosage of Sporanox is one to

four 100 mg active capsules per day, depending

on the indication.

Approximately six years into the product’s lifetime,

it was recognized that given the moderate melting

point of 166 °C for itraconazole, hot melt extrusion

(HME) technology could be used to form a solid

dispersion. This dosage form, known as Onmel, uses

Meltrex® technology. This has the advantage of allowing

a larger unit dose (e.g., 200 mg) to be delivered in

a single tablet, improving patient compliance.

Posaconazole uses hot melt extrusion (as

Noxafil). Posaconazole, a close structural analog

to itraconazole, was recognized as amenable to

HME, given its moderate melting point (172 °C),

and the fact that, as noted above, itraconazole

was successfully formulated using HME technology.

Early on, Merck (a well-known user of HME

technology) evaluated spray drying and HME as

dispersion formulation strategies for posaconazole.

Spray-dried dispersions showed improved

bioavailability, meaning that the HME dispersion

form would presumably behave in a similar manner.

Table 1: Similar in logP and logS, but data on the properties of three molecules show that similar logP and logS values differ when it comes to melting point and pKa.

Source: Data from DrugBank – Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006 Jan 1;34(Database issue): D668-72. 16381955.

Property Posaconazole Calcitriol Itraconazole

LogP 5.5 5.7 5.7

LogS (mg/ml) -1.9 -2.2 -2.0

Melting Point °C 171 113 166

pKa 3.9 Neutral 3.7

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Applying the analysis to other drugsWe can see from this analysis that clear knowledge

of first-order properties in addition to logS and

logP is necessary to define the best solubilization

technology for a given BCS Class II drug with high

permeability and low solubility. We have found that

the melting point, dose, and permeability, in addition

to the logS and logP, directly impact the suitability

of the technology.

We have analyzed data about these features across

many more compounds, and developed a tool that

provides effective solubilization technology choices

depending on the therapeutic indication targeted,

the type of molecule, the preferred delivery route,

and dosage levels. We have validated this algorithm

against commercial drugs on the market. And we are

using it now to help our clients narrow their technology

choices at the start of a project, enabling them to

minimize their costs and shorten their timelines.

While it might have been attractive to consider

a standard formulation (e.g., crystalline salt form)

for Isoptin, Accupril, and Rapumune, a clear and

thorough understanding of the molecule’s properties

improves a company’s ability to make the right

solubilization technology choice early on, leading

to faster development timelines. Also, knowing

the optimal formulation technology earlier in the

discovery process can drive better decisions about

which compound for a given project should move

forward to pre-clinical development. A robust,

scalable, and effective formulation choice in

pre-clinical development can help companies

avoid the pitfalls of reworking a formulation strategy

during Phase 2 or Phase 3 trials.

Isoptin (verapamil) is a

spray-dried dispersion.

Because of its relatively high dose,

other technologies were not

amenable. Our modeling showed

spray-dried dispersion was the best

option. Another was micronization.

HME and amorphous formulation

would have had a lower probability

of working, and the high dose

required ruled out complexes and

coated beads.

Accupril (quinapril) is an

amorphous formulation.

Our model chose this solution, and

indicated several other possibilities

due to the low dose and a favorable

melting point.

Rapumune is a lipid formulation.

Our model predicted this technology

because of the compound’s high

logP and low dose.

Here’s how our solution worked with three compounds:

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Narrowing the solubility solution searchIn recent years, drug developers evaluating solubility

solutions have focused on just two characteristics:

The logS of the compound, and its logP.

While knowing logS and logP is clearly necessary,

we need to understand and consider additional

characteristics of a poorly-soluble compound –

including melting points, potency, and dosage levels

– to determine the best solubility solution. If all factors

are not considered, many wasted cycles of effort

can be expended on formulation development. When

these efforts lead to a formulation dead end, those

costs cannot be recovered. It is better to narrow the

choices early, rather than waste time and money by

exploring many options, including those that – when

other factors are considered – are clearly unsuitable.

Manufacturability and production costs also play

a role in the selection of the ideal delivery platform

and processing technology. Any robust tool must

include these, and possibly other factors too, such

as indication, therapeutic area, chemical stability, and

thermal stability. Our tool does this. It presents viable

alternatives to minimize the chance of false negatives,

and it advises against certain technologies to

eliminate false positives.

Patheon’s model is not static. As new products

come on the market, we incorporate data about

their characteristics to revise the tool and thereby

improve its ability to predict the best solubility

solutions. We also use information contained in

new scientific literature to keep the model updated.

By using this tool early the development process,

sponsors can narrow their technology choices to the

few with the highest potential for success. That can

help them reduce their costs, improve their success

rates, and shorten their products’ time to market.

Visit patheon.com/solubilityenhancement

to discover the technologies that are most

likely to help address your molecule’s

low solubility challenges.

Patheon

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